Process for the preparation of directly compressible alpha-mannitol

ABSTRACT

The present invention relates to a process for the preparation of directly compressible mannitol having a content of the α modification of greater than 90%.

The present invention relates to a process for the preparation ofdirectly compressible mannitol having a content of the α modification ofgreater than 90% by weight.

For the production of tablets, D-mannitol can be employed as excipientmaterial for an active ingredient. To this end, the D-mannitol isusually converted into a pulverulent or granular form by a plurality ofprocess steps with corresponding interim checks in order to enable it tobe handled for tablet pressing and at the same time to facilitatebinding-in of active ingredient.

U.S. Pat. No. 3,145,146 A discloses a spray-drying process by means ofwhich mannitol is obtained in the form of fine particles having anaverage diameter of from 5 to 150 μm. A mannitol solution is spray-driedby atomisation into a stream of hot gas. The particles obtained areseparated off by suitable measures. The process described gives amixture of various crystal modifications.

It has also been disclosed that pulverulent D-mannitol can be preparedby granulation in a fluidised bed, in which the stream of process airflows through a specially shaped impingement plate, producing afluidised bed from solid starting material. The spray liquid passes intothe fluidisation space in finely divided form through a nozzle system.The fluidising particles are wetted, the surface is partially dissolved,and the particles adhere to one another. Solid is withdrawn continuouslyat the end of the fluidised bed. At the same time, a relatively smallamount of solid, onto which spray liquid is finely distributed, is fedin at the inlet. A filter system prevents dust from leaving thefluidised bed, and only granule particles which have a minimum size arewithdrawn at the exit. In addition, solid particles which have a more orless random shape form in a fluidised bed of this type. Correspondingplants are marketed by various manufacturers.

The preparation of pulverulent mannitol is usually followed by a processstep by means of which a powder having a uniform particle sizedistribution is obtained. This process step can include both grindingand screening (classification) of the powder. In the case of the use ofmannitol as excipient material for pharmaceutical active ingredients,any additional process step in the preparation represents to the personskilled in the art a possible risk of the introduction of undesiredimpurities into the product.

It is furthermore known from the literature that D-mannitol can exist inpolymorphic crystal forms; these can be the α, β and δ forms. Thedefinitions and characterisations used here correspond to theclassification of polymorphic forms by X-ray structural analysis (X-raydiffraction pattern) given in Walter Levy, L.; Acad. Sc. Paris, t. 267Series C, 1779 (1968). The β form is the most stable form, althoughconversions into the other forms are possible depending on the storagetime and the ambient conditions. For commercial applications, it istherefore desirable per se to obtain mannitol in the β form, owing toits stability, since the product properties change to the least possibleextent due to storage in this case.

It is furthermore known that on the one hand the polymorphic form inwhich the pulverulent D-mannitol exists and on the other hand the mannerin which the particle structure of the individual particles has beenbuilt up are of importance for the compression properties of thepulverulent D-mannitol. This also has a crucial influence on thepossibility of obtaining tablets in which the active ingredients presentare homogeneously distributed.

WO 97/38960 A1 describes that improved compression properties arisethrough partial or complete conversion of the pulverulent D-mannitolfrom the δ form into the β form. Conversion from the δ form into the βform is caused by targeted wetting of the particle surfaces of thepowder with a water-soluble solvent or water and by subsequent drying.The percentage of β-mannitol formed is dependent on the amount ofsolvent employed and the duration of the drying operation. A mixture ofδ and β forms is therefore usually present in the product.

It is disadvantageous in this process that the conversion is anadditional process step which follows the actual powder preparation, andthe drying requires at least 8 hours, during which the plant has to becontinuously supplied with thermal energy.

In contrast to the δ and β modification forms described, α-mannitol hashitherto principally been isolated from the melt. This process islabour- and energy-intensive. The product obtained in this way has poorcompression properties.

The object of the present invention is therefore to provide a processfor the preparation of directly compressible α-mannitol which can becarried out in a simple manner.

The object of the invention is also to provide a process by means ofwhich, in a first step, directly compressible α-mannitol is prepared,which, in subsequent process steps, is incorporated into formulationscomprising active ingredient and can be converted into β-mannitol in asimple manner for homogeneous and stable binding-in of the activeingredient.

The object is therefore achieved by a process for the preparation ofdirectly compressible α-mannitol having a content of the α modificationof greater than 90%, in which

-   a) in a first step, an aqueous D-mannitol solution as starting    material, spray gas, pulverulent α-mannitol and hot gas are    combined,-   b) the resultant pulverulent product is precipitated into a    fluidised bed, taken up, fluidised and transported further, and-   c) some of the pulverulent product formed is recycled into the    process.

In a particular embodiment of the process, the resultant powder is, inone or more granulation step(s), sprayed with further liquid medium,dried and transported further in the fluidised bed.

For the preparation of the mannitol solution, use is made of D-mannitolhaving a purity of >90%, preferably >95%. Use is particularly preferablymade of D-mannitol having a purity of >98%.

Surprisingly, the equilibrium can be shifted towards the formation ofα-mannitol by recycling the α-mannitol formed as the dust fraction fromthe product discharge zone of the processor into step a) of the spraydrying. In a particularly advantageous embodiment of the process,α-mannitol having a mean particle size of less than 20 μm, in particularhaving a mean particle size in the range from about 1 to 20 μm,preferably in the range from 3 to 15 μm, is recycled.

The recycling of the “dust-form” α-mannitol formed as pulverulentα-mannitol from the powder-metering device in line (9A) is effected bycontrolling the rotational speed of the star valve 10A via the fan (E)into the spray drying (step a).

After the equilibrium has been established, it is readily possible torecycle pulverulent α-mannitol having a mean particle size of less than75 μm.

The particular design of the plant used enables the recycled pulverulentmaterial to be comminuted, before the recycling, by grinding in the fan(E), which simultaneously serves as conveying element for the powderrecycling.

Regulation of the rotational speeds of the star valves 10A and 10B ofthe plant used and grinding of the coarse (oversize) product formed toparticle sizes of less than 75 μm in the fan (E) before recycling intothe spray drying result in the exclusive formation of α-mannitol.

In order to carry out the process, an aqueous, at least >45%,preferably >50% D-mannitol solution is employed as starting material andis atomised at a temperature in the range from 60 to 95° C.

Air or an inert gas selected from the group consisting of N₂ and CO₂ canbe used both as spray gas and as carrier and heating gas. The gas ispreferably circulated in the process according to the invention, and thecirculated gas is freed from particles by filters, dried in thecondenser and fed back to the spray nozzles or heated and introducedinto the fluidised bed.

The circulated gas is preferably freed from particles with the aid ofdynamic filters.

In a particular embodiment of the process, the liquid media used havedifferent compositions at different points of the plant.

Particle sizes of between 50 and 1000 μm can be produced specifically inthe process according to the invention by varying the process parametersof spray pressure, spray amount, mannitol concentration, amount ofpowder recycled, hot-air stream and hot-air temperature.

For this purpose, the air fed to the plant is, in accordance with theinvention, pre-heated to a temperature in the range 45-110° C. and theamount of feed air supplied is set in the range 1000-2000 m³/m² perhour, giving a waste-air temperature of at least 40° C., preferably inthe range 40-60° C. At the same time, the spray pressure of thetwo-component nozzles is set in the range 2-4 bar, so that from about1.5 to 3 m³/(h kg of solution) of hot gas are fed to the two-componentnozzle, with the temperature of the hot gas being set in the range fromabout 80 to 110° C. Good process results are obtained if the powderrecycling is regulated in such a way that recycling is carried out in anamount in the range 0.2-2.0 kg of solid/(h kg of solution).

Particularly uniform formation of pulverulent product having anα-mannitol content of >95% is carried out by adjustment of theparameters of spray pressure, amount of liquid, mannitol concentration,amount of powder recycled, hot-air stream and hot-air temperature,through which the amount of powder present in the fluidised bed is setto an amount in the range 50-150 kg/m² of bed.

Through experiments, a process has been found for the preparation ofpure α-(D)-mannitol by means of which directly compressible mannitol (DCmannitol) having a suitable homogeneous particle size distribution canbe prepared. The process is carried out using mannitol having a purityof greater than 98%, where the remainder can be sorbitol and otherresidual sugars. An aqueous solution having a mannitol content of aboutat least 45% by weight is prepared. Use is usually made of solutionshaving a mannitol content in the range 45-60% by weight. The solutionprepared is atomised in a spray-drying plant at a feed-air temperatureof about 60-110° C. and dried. For this process step, use is preferablymade of an aqueous solution having a mannitol content of greater than50% by weight. Through experiments, it has been found that the use ofsolutions comprising more than 60% by weight of mannitol is alsopossible under certain conditions and products having an α-mannitolcontent of >95% by weight are obtained

The process is carried out using a plant as described in DE 1 99 27 537,but with a slight modification. By means of the plant described in thispatent application, it is possible per se to vary the properties ofspray-dried or granulated, pulverulent products as desired with respectto particle size, particle size distribution, moisture content andcompressibility. However, the changes to the plant enable additionalfine adjustment through the powder recycling.

In particular, the process is carried out in a spray-drying plant whichcomprises

-   a) a spray-drying unit (B),-   b) a fluidised bed (A),-   c) one or more additional spray or atomisation nozzles for liquid    media (C),-   e) a powder-metering device (D) and-   f) a powder recycling system (9) with fan (E), where the lines (9A)    and (9B) intended for powder recycling are provided with star valves    (10A, 10B), and the powder (8) which does not enter the    powder-metering device can be separated into a dust-form fraction    and a coarse fraction.

In the spray-drying unit (B) of the plant used in accordance with theinvention, the liquid medium (5), spray gas (6), pulverulent material(9) and hot gas (4) are combined.

In a particular embodiment, a spray-drying unit (B) is locatedvertically above a subsequent horizontal fluidised bed in a spray tower.

In a particular embodiment, the spray-drying unit (B) of the plant cancomprise a spray system which consists of a two-component spray nozzleheated by means of hot water with coaxially arranged powder recyclingand surrounding hot-gas flow.

In the plant used, one or more additional spray or atomisation nozzlesfor liquid media (C) can be installed in the fluidised bed, also withvariable location. The fluidised bed is followed by a powder-meteringdevice (D), which is separated off by a valve flap (F) and which is fedby a product overflow (8). Some of the product formed can be recycledinto the spray-drying unit (B) via fly conveying, in which a fan (E)serves as conveying element, if desired after comminution (9A, 10A) orwithout comminution (9B, 10B). The fan (E) acting as conveying elementcan simultaneously serve as comminution unit for the recycled powder.

In the process for the preparation of spray-dried pulverulentα-(D)-mannitol,

-   a) in a first step, a liquid medium, spray gas, pulverulent material    and hot air are combined,-   b) the existing pulverulent product is precipitated into a fluidised    bed, taken up, fluidised and transported further, and, if desired,-   c) in one or more granulation step(s), sprayed with further liquid    medium, dried-   d) and conveyed in the fluidised bed in the direction of the    powder-metering device, from which-   e) some of the unground and/or ground, pulverulent material is    recycled into the process.

The liquid medium is preferably a solution. However, it may also be anaqueous suspension of pre-formed α-(D)-mannitol, but this has to beatomised immediately after its preparation since α-(D)-mannitol isunstable in the presence of water and rearranges to the β form.

In a particular variant of the process, the recycled pulverulentmaterial can be comminuted before the recycling.

The spray, carrier and heating gas used can be air or an inert gasselected from the group consisting of N₂ and CO₂. The gas can, inaccordance with the invention, be circulated, it being freed fromparticles by filters or especially with the aid of dynamic filters,dried in the condenser and fed back to the spray nozzles or heated andintroduced into the fluidised bed.

In order to carry out the process, the plant is initially charged withpulverulent starter material via the fill ports (3). A stream of air isproduced in the spray-drying space via the chambers (1). The introducedstarter material is fluidised by this stream of air and moves in thedirection of the discharge flaps (F). The powder stream attains thisdirection of movement on generation of the air stream through acorresponding perforation of the Conidur plate. The fluidised productcan be discharged by simply opening the valve flaps (F). At this pointof the plant, devices are provided which enable the product to berecycled either into a powder-metering device or, via fly conveying, tothe spray-drying unit. An overflow (8) for the finished product islocated at the discharge above the powder-metering device. The fan (E)of the spray-drying unit serves both as conveying means for the productand as comminution unit for powder material to be recycled. Recycledpowder material from the return line (9A, 9B) is combined with thecorresponding media liquid (5), spray air (6) and hot air (4) throughthe particular design of the spray-drying nozzle. The correspondingpowder or granular material is taken up by the fluidised bed and, asalready described above, transported further. On passing through thegranulation nozzles (C), further medium, which can have a differentcomposition to that introduced into the spray nozzle with powderrecycling, can be sprayed onto the particles formed. In this way,further granulation and re-setting of the particle size distribution cantake place. The product from the chambers (1) is dried to the desiredfinal moisture content by means of air introduced via the Conidurplates. Dynamic filters (G) integrated into the plant prevent dischargeof powder particles into the environment.

Instead of the granulation nozzles (C), as shown in FIG. 1, one or morespray nozzles or spray-drying nozzles or alternatively only one, two ormore than three granulation nozzles can be installed at thecorresponding point of the plant. These additional nozzles may belocated directly at the beginning of the fluidised bed or moved furtherto the back. The choice of site at which the powder material originallyformed is re-sprayed one or more times is, inter alia, also dependent onthe residual moisture content that the desired product is to have. Itgoes without saying that a product having a particularly low residualmoisture content after the final spraying makes a longer residence timein the fluidised bed necessary than one having a higher residualmoisture content.

As desired, different compositions can be applied through the variousnozzles to the particle surfaces already formed, enabling particleshaving a layered structure to be obtained. However, it can also serve toachieve a more uniform particle size distribution.

It is furthermore possible to operate the plant not only with air ascarrier medium. It is also possible to operate the entire plant incirculation with an inert gas, such as, for example, nitrogen or carbondioxide.

The plant is designed in such a way that the parameters amount ofliquid, spray pressure, amount of powder recycled, amount of hot gas,hot-gas temperature, amount of warm air, warm-air temperature, etc., canbe regulated individually. The amount of powder recycled, the amount ofliquid fed in and the spray pressure can therefore be set specificallydepending on the desired properties with respect to moisture content,particle size and particle size distribution of the end product. Asdesired, pulverulent products having particle sizes of between 50 and1000 μm can be produced in the plant described. Depending on theprocedure and the process parameters selected, the particles can have alayered (onion) structure or an agglomerate structure.

The formation of the particles can be controlled particularly by a spraynozzle integrated into the plant, which is suitable for the productionof spray-dried granules. This spray nozzle is a spray system (B) whichconsists of a two-component spray nozzle [(1), (2), (3)], which can beheated by means of hot water and which is in turn fitted with a powderrecycling system (4) arranged around the two-component spray nozzle anda surrounding hot-gas flow (5). Specifically, the powder recyclingsystem (4) can be arranged coaxially around the two-component spraynozzle.

The advantage of this spray system is that recycled powder comes intocontact immediately at the exit of the two-component spray nozzle withthe liquid droplets generated via the atomisation air. In order that thepowder particles do not stick together and that the surface moisture canbe drawn off, the spray and powder part of the spray nozzle with powderrecycling is included in a hot-gas stream. Subsequent drying to thedesired residual moisture content takes place in the fluidised bed.

In particular also through the incorporation of this spray-dryingsystem, it is possible to produce certain particle sizes specifically.

A particular advantage of this spray-drying process therefore consistsin that pulverulent α-(D)-mannitol having very different properties withrespect to moisture content, particle size, particle size distribution,bulk density and particle structure can be prepared in a single plantwithout further process steps for aftertreatment of the productdepending on the process parameters set and on the liquid media to beatomised.

In order to obtain particularly good DC properties (DC=directlycompressible) of the spray-dried substance, here α-(D)-mannitol, it isadvantageous to agglomerate the individual particles formed in the spraydrying. For this purpose, a spray tower is located vertically above thefluidised bed above the spray-drying unit (B) according to theinvention. In the depicted variant of the possible plant design, thefluidised bed is preferably constructed lying horizontally, in which theproduct is transported to the exit by the air stream that has been set.

The hot aqueous mannitol solution is atomised via one or moretwo-component nozzle(s) (5) (6), which is (are) heated with hot water(7). The spray jet produced is surrounded by a mannitol powder recyclingsystem (9) arranged around this nozzle and a stream of hot gas (4). Thesolid crystallises in the spray jet, forms agglomerates and is taken upby the fluidised bed. Hot air from the air introduction chambers (1)flows through the fluidised bed and fluidises the latter. The base ofthe fluidised bed is a Conidur plate, which ensures specific transportof the solid in the direction of the discharge and also produces adefined residence time of the solid in the fluidised bed. The residencetime of the product in the processor can furthermore be controlled viathe bed depth, spray amount and recycle quantity. The solid istransported through a plurality of air introduction chambers (1)connected in series and dried to a residual moisture content of <0.3%.The drying operation takes place over the length of the fluidised bed ina certain temperature profile in order to prevent overheating of theproduct.

The water-laden and dust-containing fluidisation air is cleaned viadynamic filters (G) and discharged via the waste-air chambers (2). Thedynamic filters are regularly cleaned by means of pulses of compressedair. The dust cleaned off binds the spray mist from the spray zone andprevents settling and baking of solid onto the walls.

The dried solid falls into a metering system for recycling (D) viadouble pendulum flaps (F) or other discharge systems. The dischargedproduct can optionally be worked up further via a classification system.The oversize particles (and undersize particles) formed can be ground inthe fan (E) above the powder recycling system (9) and recycled into thespray drier together with the undersize particles, i.e. with dust-formmannitol powder having particle sizes of less than 75 μm, in particularless than 40 μm.

A sub-stream is discharged as finished product (8) at the discharge. Theproduct can be classified via a sieve, it being possible for theoversize particles (residual material or the coarse powder fraction) tobe recycled via the suction side of the grinding fan (9A), ground andreturned to the process. Inter alia, this minimises product losses.

The fan (E) of the spray-drying unit serves both as conveying means forproduct to be recycled (introduction of solid on the pressure side (9B))and as comminution unit for recycled powder material (introduction ofsolid on the suction side (9A)). The two sub-streams of solid arecontrolled, for example, via the rotational speed of the star valves(10A, 10B). Recycled powder material from the return lines (9) is, asalready described above, combined with the corresponding media liquid(mannitol solution) (5), spray air (6) and hot air (4) through theparticular design of the spray-drying nozzle.

The feed air is fed to the fan (E) from the product discharge zone ofthe processor. In this way, the fine dust (<15 μm) is removed from theproduct at the same time (pneumatic classification). At the same time,the removal of this fine dust has the effect that greater tablethardness values can be achieved on use of this product freed from finedust.

In the case of sub-stream 9B, the option exists of screening theoversize particles (residual material) out of the recycling system afterthe star valve 10B in order to be able to control the process better.These oversize particles (residual material) can be introduced on thesuction side into the grinding fan (E) or another comminution machine,ground and fed back to the process.

As already indicated above, the quality of the agglomerates and thus ofthe product can be controlled via the plant parameters, such asconcentration, spray pressure, temperature, spray amount, amount ofrecycled powder, amount of principal air, dust extraction, bed depth,etc. A reduction in the height of the spray nozzle [(B)→(C)] above thefluidised bed enables the particle structure to be converted from anagglomerate (berry structure) into granules (onion structure). With thelowest possible arrangement of the nozzles (granulation nozzles (C)),the powder recycling (9) can take place via the fill ports (3). In orderto obtain a directly compressible product continuously, both theparticle structures and the modification, particle size distribution,water content, density, etc., must be monitored. It has been found thatthe best product for compression is obtained if mannitol is crystallisedout in a fine needle structure.

Experiments have shown that it is necessary to maintain and monitor theset parameters of the spray-drying process in order to obtain pureα-mannitol which has constant, good compression properties.

In the preparation of a formulation, the DC α-mannitol is homogenisedwith the active ingredient in a mixer and can immediately be compressedto form a tablet. The intermediate steps of agglomeration or granulationwith subsequent classification and drying are saved. The conversion ofthe α modification into the β modification can be controlled through theaddition of water and the residence time. In the case of some activeingredients, this conversion has the advantage that they are bound intothe grain structure of the mannitol.

In accordance with the invention, the starting material employed ispreferably D-mannitol having a purity of >90%, particularly preferablyhaving a purity of >95% and very particularly preferably having a purityof >98%. This starting material is employed in the form of anaqueous >40-50% solution and is atomised into the plant at a temperaturein the range from 60 to 95° C. The solution is preferably heated to atemperature in the range from 70 to 95° C., in particular from 75 to 90°C., before the atomisation.

In accordance with the invention, solutions having different mannitolconcentrations can be employed at different points of the plant. Thus,it has proven appropriate to charge spray nozzles above the fluidisedbed in the direction of the product discharge with solutions havinghigher mannitol concentrations than spray nozzles located at thebeginning of the fluidised bed. It is therefore possible to employ asolution having a mannitol concentration of about 60% by weight, basedon the solution as a whole, at the end of the fluidised bed, whereas thetwo-component nozzle with powder recycling is preferably operated withan at least 45% by weight aqueous solution. In this way, the productproperties can again be influenced in the desired sense, it beingnecessary to observe the plant parameters precisely in this procedure.

Through variation of the parameters spray pressure, amount of liquid,amount of powder recycled, hot-air stream and hot-air temperature,particle sizes of between 50 and 1000 μm can be set specifically.

It has furthermore been found that the parameters of the plant used inaccordance with the invention have to be set as follows in order toobtain a uniform product:

The spray pressure of the two-component nozzles should be set in therange 2-4 bar, preferably in the range from 2.5 to 3.5 bar.

The amount of hot gas fed to the two-component nozzle should beregulated in such a way that from about 1.5 to 3 m³/(h kg of solution)at a temperature of from about 80 to 110° C. are conveyed. It has beenfound that, with a relatively high feed of hot gas, better productquality is obtained if a relatively low temperature is used.

The powder recycling should be set in accordance with the invention insuch a way that solids recycling takes place in the range 0.2-2.0 kg ofsolid/(h kg of solution), preferably in the range from 0.5 to 1.5 kg ofsolid/(h kg of solution). The process is particularly favourable if thesolids recycling is in the range from 0.5 to 1.0 kg of solid/(h kg ofsolution).

In order to carry out the process, pre-heated air must be fed into theplant. Good results are achieved if the air fed to the plant ispre-heated to a temperature in the range 45-120° C. It is favourable forthe process according to the invention if the feed air has a temperaturein the range from 65 to 110° C. It is particularly advantageous for theformation of an α-mannitol powder having good compression properties ifthe temperature of the feed air fed in is in the range from 70 to 110°C.

The amount of feed air supplied should be regulated in accordance withthe invention in such a way that 1000-2000 m³/m² per hour, in particularfrom 1200 to 1700 m³/m² per hour, are fed into the plant.

In combination with the other parameters set, favourable processconditions exist if the air stream is fed in the plant in such a waythat the waste-air temperature is in the region above 40° C.

It has furthermore proven favourable to regulate the process conditionsin such a way that the amount of powder located in the fluidised bed isset to an amount of 50-150 kg/m² of bed. It is particularly favourableif the amount of powder is in the range 80-120 kg/m² of bed.

It has also been found that the process can be controlled, inparticular, by specific recycling of a powder having a selected particlesize.

As can be seen from the plant diagram (FIG. 1), powder recycling can becarried out both by powder withdrawal from the fluidised bed and byrecycling of a very finely divided powder fraction which is formedduring finishing, i.e. during homogenisation of the particle size byscreening and packaging of the resultant product.

It is also possible, prior to recycling, to comminute powders havingrelatively large particle cross sections in the fan (E) of thespray-drying unit. As already indicated above, the powder stream can becontrolled by adjusting the rotational speed of the star valves (10A,10B). In order to grind powder to be recycled to the desired particlesize before the recycling, the rotational speed of the star valve 10A(B) should accordingly be set in such a way that recycling takes placevia the fan with grinding.

Experiments have shown that the equilibrium can be shifted towards theformation of α-mannitol if the mean particle size of the recycled powderground in the fan (E) is less than 75 μm. α-mannitol is particularlypreferably formed if the mean particle size of the recycled powder isless than 40 μm. Surprisingly, it has been found that recycling of apowder having particle sizes of less than 20 μm gives mannitol powdershaving a proportion of the α-fraction of greater than 90%. It hasparticularly surprisingly been found that, in particular, recycling ofthe so-called dust fraction which is formed in the product dischargezone of the processor and is usually removed from the product results ina uniform product having a particularly high proportion of theα-fraction. The mean particle size of the dust fraction is in the rangefrom about 1 to 20 μm, in particular in the range from 3 to 15 μm. Inaddition, it has been found that the dust from the recycling results instable operation in the spray zone of the processor.

Since grinding in the fan (E) only gives these particle sizes withparticular effort, the “dust-form” product fraction from thepowder-metering device, which is formed in the plant in line (9A), ispreferably recycled into the spray drying, in particular at thebeginning of the process, by controlling the rotational speed of thestar valve 10A by grinding. By simultaneously reducing the rotationalspeed of the star valve 10B, recycling of coarse mannitol fraction isreduced.

Surprisingly, it has been found that, after the equilibrium has beenestablished in the direction of the formation of α-mannitol in a purityof greater than 95%, the process can be continued in a stable manner ifthe powder ground in the fan to a particle size of less than 75 μm islikewise recycled.

In this way, it is possible, surprisingly, to set the spray-dryingprocess by exclusive recycling of the “dust fraction” formed byregulation of the rotational speeds of the star valves 10A and 10B atthe beginning in such a way that only α-mannitol is formed. Therelatively coarse fraction (the so-called oversize particles) of themannitol powder formed can subsequently again also be recycled into theprocess without risking shifting the equilibrium. This has the advantagethat adhesion of the particularly finely divided spray mist to the wallsof the plant in long-term operation can be avoided and interruptions tothe process can be prevented.

A suitable choice of the process parameters enables production of aproduct having a content of the α modification of greater than 90%.Constant monitoring of the product quality produced enables the fractionto be increased readily to a content of the α modification to greaterthan 95%.

In particular if the above-described plant parameters are set to theoptimum and the other process parameters are monitored, the productobtained in the process according to the invention is a mannitol havingthe following properties:

-   -   directly compressible mannitol    -   purity of the α modification >95%    -   bulk density 350-500 g/l    -   residual moisture content <0.3%    -   particle distribution: x₅₀ at 200 μm: <10%<53 μm+<15%>500 μm    -   x₅₀ at 300 μm: <10%<100 μm+<10%>850 μm    -   x₅₀ at 450 μm: <5%<100 μm+<10%>850 μm

Since the various modifications of the mannitol are very similar, theycannot be differentiated in the DSC on the basis of their melting pointsusually measured in analysis. Identification is only possible, forexample, by means of X-ray or NIRS.

However, owing to the tablet hardness values achieved with the resultantproduct, significant differences from commercially available productsare evident. Compared with a commercially available product which has arelatively high content of the α modification in the pulverulentmannitol, tablets having hardness values which are from about 45 to 70%higher are obtained with the α-mannitol prepared in accordance with theinvention.

During storage of DC α-mannitol, it must be ensured that the atmosphereis dry. It is advantageous to carry out the storage of the DC α-mannitolin a WPC with PE bag and integrated desiccant, since the PE bag is notpermeable to water vapour. Moisture converts the α modification of themannitol into the β modification. Under the above-described conditions,storage of the DC α-mannitol for a number of years is possible.

Through experiments, it has furthermore been found that, compared withthe δ form of mannitol, α-mannitol can be converted into the β form in asimple manner by addition of moisture. For this purpose, water is addedin order to control the conversion of α-mannitol into β-mannitol throughthe addition and the residence time in this process step. It must benoted here that the mannitol particles may be modified if water is addedin too great an amount and too quickly.

For homogeneous binding-in of active ingredients, the active ingredientis, in a first step after preparation of the directly compressibleα-mannitol, introduced into a suitable mixer and homogenised with theα-mannitol.

In the preparation of a formulation, the DC α-mannitol is homogenisedwith the active ingredient in a mixer and can immediately be compressedto form a tablet. The conversion of the α modification into the βmodification can be controlled through the addition of water and theresidence time. In the case of some active ingredients, this conversionhas the advantage that they are bound into the grain structure of themannitol.

For better understanding and in order to illustrate the invention, ageneral flow chart (FIG. 1) of the spray-drying plant described is givenbelow, along with examples which are within the scope of protection ofthe present invention.

FIG. 1 shows a generalised flow chart of a possible embodiment of aspray-drying plant employed for carrying out the process, in which thenumbers and letters given have the following meanings: 1 Airintroduction chambers 2 Heating devices 3 Fill ports 4 Hot-air feed 5Liquid feed 6 Spray air 7 Heating medium 8 Product 9 Powder (9A finelydivided powder (dust), 9B coarse powder) 10 Star valve (10A and 10B) forregulating the powder recycling A Fluidised-bed apparatus B Spray-dryingunit C Granulation nozzles D Powder-metering device E Fan for powderrecycling F Valve flaps G Dynamic filter

With reference to the components mentioned in the description and givenin the flow chart, it is readily possible for the person skilled in theart to produce an appropriate plant for carrying out the process byselecting commercially available individual components. It goes withoutsaying for the person skilled in the relevant art that both additionalelectrical and mechanical control units have to be installed foroperation of the plant in order to be able to regulate and vary theparameters in the process according to the invention, as described.

For better understanding and in order to illustrate the invention,examples are given below of the preparation of directly compressibleα-mannitol and of illustrative formulations in which the activeingredient is bound in the mannitol by conversion of the α modificationinto the β form. Both the examples and the flow chart are unsuitable forrestricting the scope of protection of the present application to thesealone, since it is readily possible for the person skilled in the art tocarry out a very wide variety of variations in the design of the plantand to replace individual parts of the plant by devices having anequivalent action. It is also readily possible for him to carry out thegiven examples in a suitable manner in α modified form and likewise toachieve the desired result.

The following examples for the preparation of various DC β-mannitolgrades serve to explain the present invention in greater detail.

EXAMPLES Example 1

Preparation of a DC α-mannitol Having a Mean Particle Size X₅₀=200 μm

For preparation, the spray-drying plant is filled with about 70 kg/m² ofα-mannitol as the bed. (This initially introduced bed should as far aspossible have the desired product properties. If the bed materialavailable should have other properties, the plant must be started upunder gentle conditions until the equilibrium has shifted in the desireddirection).

As fluidisation and feed air, the plant is operated with 1200 m³/m² h ata temperature of above 90° C. (Before start-up of the plant, it must beensured that sufficient dust is present in the plant. Dust can begenerated via the powder-metering device (D), the suction-side recyclingsystem (9A) and metering device (10A) via the/with the fan (E) and blowninto the plant). When sufficient dust is in the plant, the metering(10A) of the recycle is reduced, and the atomisation of mannitolsolution is begun. The atomised solution has a concentration of about45% and a temperature of about 75° C. At a spray pressure of about 3 bar(spray medium is air), about 45 kg/m² h of solution are atomised in theplant. About 0.5 kg of solid/(h kg of solution) is recycled into thespray zone via the recycling system (9, 10) via the powder-meteringdevice (D). The star wheels (10A, 10B) are set in such a way that asufficient amount of product (9A, 10A) is always ground in the fan (E)and conveyed back into the plant with the unground product (9B, 10B).

Evaporation of the water in the plant causes the formation of anequilibrium with a bed temperature of above 45° C. The waste-airtemperature is above 40° C. (It must be ensured that the waste air issaturated as far as possible. This is advantageous for the efficiency ofthe process and for the mannitol crystallisation process). In this way,the best crystal structure and the purest α modification of the mannitolare obtained. Since the fan (E) takes its feed air from the productdischarge zone before the valve flaps (F) of the plant (A), and thedischarged product is thus dust-free due to the pneumaticclassification, α-mannitol with excellent properties for directcompression is obtained at the product discharge (8). In order to obtainDC α-mannitol having the desired particle size distribution, it can besieved after the discharge valve (F), i.e. before the product discharge(8) and the powder-metering device (D). It is advantageous for theprocess also to sieve the oversize particles out of the product to berecycled (9B, 10B), since they otherwise accumulate further in the sprayzone and can cause problems in the fluidised bed. The undersize andoversize particles sieved out can be fed on the suction side to the fan(E), ground and fed back into the process together with the otherrecycled solids sub-streams (9A, 10A, 9B, 10B). In this way, productlosses are minimised, and the process runs in a more stable mannerthrough the additional dust recycling (ground product).

Example 2

Preparation of a DC α-mannitol Having a Mean Particle Size X₅₀=300 μm

As described in Example 1, the spray-drying plant is, for preparation,filled with about 100 kg/m² of α-mannitol as the bed and started up.

As fluidisation and feed air, the plant is operated with 1500 m³/m² h ata temperature of above 90° C. The mannitol solution to be atomised has aconcentration of about 50% at a temperature of about 80-90° C. At aspray pressure of about 3 bar (spray medium is air), about 65 kg/m² h ofsolution is atomised in the plant. The star wheels (10A, 10B) are set insuch a way that a sufficient amount of product (9A, 10A) is alwaysground in the fan (E) and conveyed back into the plant with the ungroundproduct (9B, 10B). Evaporation of the water in the plant causes theformation of an equilibrium with a bed temperature of about 45° C. Thewaste-air temperature is about 40-45° C. It must be ensured that thewaste air is saturated as far as possible. The oversize particles fromthe product to be recycled (9B, 10B) are sieved out, since theyotherwise accumulate further in the spray zone and cause problems in thefluidised bed. The undersize and oversize particles sieved out are fedon the suction side to the fan (E) and ground. They are fed back intothe process together with the other recycled solids sub-streams (9A,10A, 9B, 10B).

Example 3

Preparation of a DC α-mannitol Having a Mean Particle Size X₅₀=450 μm

As described in Example 1, the spray-drying plant is, for preparation,filled with about 120 kg/m² of α-mannitol as the bed. As fluidisationand feed air, the plant is operated with 1700 m³/m² h at a temperatureof about 100° C.

The hot gas is fed to the spray zone in an amount in the order of about1.6 m³/(h kg of solution) at a temperature of about 100° C. When allthese parameters have been set, atomisation of mannitol solution can bebegun.

The solution has a concentration of above 55% by weight at a temperatureof about 90-100° C. At a spray pressure of about 3.5 bar (spray mediumis air), about 100 kg/m² h of solution are atomised in the plant.Bed/product of about 0.8-1.0 kg of solid/(h kg of solution) is recycledinto the spray zone via the powder-metering device (D) via the recyclingsystem (9, 10). The star wheels (10A, 10B) are set in such a way that asufficient amount of product (9A, 10A) is always ground in the fan (E)and conveyed back into the plant with the unground product (9B, 10B).

Evaporation of the water in the plant causes the formation of anequilibrium with a bed temperature of about 40-50° C. The waste-airtemperature is about 40-45° C. It must be ensured that the waste air issaturated as far as possible.

The oversize particles from the product to be recycled (9B, 10B) aresieved out since they otherwise accumulate in the spray zone and causeproblems in the fluidised bed. The undersize and oversize particlessieved out are fed on the suction side to the fan (E) and ground. Theyare fed back into the process together with the other recycled solidssub-streams (9A, 10A/9B, 10B).

1. Process for the preparation of directly compressible mannitol havinga content of the α modification of greater than 90%, characterised inthat a) an aqueous D-mannitol solution, spray gas, pulverulent(α-mannitol and hot gas are combined, with air or an inert gas selectedfrom the group consisting of N₂ and CO₂ being used both as spray gas andas carrier and heating gas, b) the resultant pulverulent product isprecipitated into a fluidized bed, taken up, fluidised and transportedfurther, and c) some of the pulverulent product formed is recycled intothe process, and optionally d) the resultant powder is, in one or moregranulation step(s), sprayed with further liquid medium, dried andtransported further in the fluidised bed.
 2. Process according to claim1, characterised in that, for the preparation of the mannitol solutionemployed, use is made of D-mannitol having a purity of >90%,preferably >95%.
 3. Process according to claim 1, characterised in that,for the preparation of the mannitol solution employed, use is made ofD-mannitol having a purity of >98%.
 4. Process according to claim 1,characterised in that the α-mannitol formed as dust fraction in theproduct discharge zone of the processor is recycled into step a) of thespray drying, and the crystallisation equilibrium is shifted towards theformation of α-mannitol.
 5. Process according to claim 4, characterisedin that α-mannitol having a mean particle size of less than 20 μm, inparticular having a mean particle size in the range from about 1 to 20μm, preferably in the range from 3 to 15 μm, is recycled.
 6. Processaccording to claim 4, characterised in that the “dust-form” α-mannitolformed in line (9A) is recycled into the spray drying (step a)) from thepowder-metering device as pulverulent α-mannitol by controlling therotational speed of the star valve (10A) via the fan (E).
 7. Processaccording to claim 1, characterised in that, after the equilibrium hasbeen established, pulverulent α-mannitol having a mean particle size ofless than 75 μm is recycled.
 8. Process according to claim 1,characterised in that, after the equilibrium has been established,pulverulent unground α-mannitol is recycled.
 9. Process according toclaim 7, characterised in that the recycled pulverulent material iscomminuted, before the recycling, by grinding in the fan (E), whichsimultaneously serves as conveying element for the powder recycling. 10.Process according to claim 1, characterised in that regulation of therotational speeds of the star valves 110A and 10B and grinding of thecoarse product formed to particle sizes of less than 75 μm in the fan(E) before recycling into the spray drying result in the exclusiveformation of α-mannitol.
 11. Process according to claim 1, characterisedin that an aqueous 45-60% D-mannitol solution is employed as startingmaterial and is atomised at a temperature in the range from 60 to 95° C.12. Process according to claim 1, characterised in that the gas iscirculated, and the circulated gas is freed from particles by filters,dried in the condenser and fed back to the spray nozzles or heated andintroduced into the fluidised bed.
 13. Process according to claim 12,characterised in that the gas is freed from particles with the aid ofdynamic filters.
 14. Process according to claim 1, characterised in thatthe liquid media used have different compositions at different points ofthe plant.
 15. Process according to claim 1, characterised in thatparticle sizes of between 50 and 1000 μm are produced specifically byvarying the parameters of spray pressure, spray amount, mannitolconcentration, amount of powder recycled, hot-air stream and hot-airtemperature.
 16. Process according to claim 15, characterised in thatthe air fed to the plant is pre-heated to a temperature in the range45-120° C. and the amount of feed air fed in is fed in the range1000-2000 m³/m² per hour, giving a waste-air temperature in the regionof above 40° C.
 17. Process according to claim 15, characterised in thatthe spray pressure of the two-component nozzles is set in the range 2-4bar, and from about 1.5 to 3 m³/(h kg of solution) of hot gas having atemperature of from about 80 to 110° C. are fed to the two-componentnozzle.
 18. Process according to claim 15, characterised in that thepowder recycling is carried out in an amount in the range 0.2-2.0 kg ofsolid/(h kg of solution).
 19. Process according to claim 15,characterised in that the amount of powder present in the fluidised bedis set to an amount in the range 50-150 kg/m² of bed by adjustment ofthe parameters spray pressure, amount of liquid, mannitol concentration,amount of powder recycled, hot-air stream and hot-air temperature.